Project Summary: Inflammation underlies the disabling manifestations and co-morbidities of rheumatoid arthritis (RA). Genetic differences in the regulation of inflammatory signaling between individuals are highly relevant and significant as such differences likely determine those individuals that will progress to RA, the severity of their disease, and even influence the treatment options that will be palliative. Much of our understanding of the pathophysiology of RA is based in part on animal models. However, recent work demonstrates that humans posses seven genes coding Pyrin-only and CARD-only proteins (POPs and COPs) that limit NF-kB signaling and infammasome activation pathways, events critical for elaboration of the cytokines mediating inflammation. We have identified an allele of POP2 associated with severe, and likely treatment resistant RA. Evaluating the function of this RA-associated allele in vivo and in vitro will help reveal the immunological and molecular basis for the association and provide insight into why some RA patients develop severe RA resistant to otherwise effective treatment with sophisticated biologics targeting TNF and IL-6. Such knowledge could help guide clinical decision making and advance efforts to identify new therapeutic modalities. This application proposes a transgenic mouse model and cellular tools to investigate the nature of the POP2 allele associated with RA. These tools are a necessary first step towards further investigation of the function of POP2 in RA disease.